The Kv3 voltage-gated potassium channel family includes four members, Kv3.1, Kv3.2, Kv3.3, and Kv3.4. Genes for each of these subtypes can generate multiple isoforms by alternative splicing, producing versions with different C-terminal domains. Thirteen isoforms have been identified in mammals to date, but the currents expressed by these variants appear similar (Rudy and McBain, 2001, Trends in Neurosciences 24, 517-526). Kv3 channels are activated by depolarisation of the plasma membrane to voltages more positive than −20 mV; furthermore, the channels deactivate rapidly upon repolarisation of the membrane. These biophysical properties ensure that the channels open towards the peak of the depolarising phase of the neuronal action potential to initiate repolarisation. Rapid termination of the action potential mediated by Kv3 channels allows the neuron to recover more quickly to reach sub-threshold membrane potentials from which further action potentials can be triggered. As a result, the presence of Kv3 channels in certain neurons contributes to their ability to fire at high frequencies (Rudy and McBain, 2001, Trends in Neurosci. 24, 517-526). Kv3.1-3 subtypes are predominant in the CNS, whereas Kv3.4 channels are found predominantly in skeletal muscle and sympathetic neurons (Weiser et al., 1994, J. Neurosci. 14, 949-972). Kv3.1-3 channel subtypes are differentially expressed by sub-classes of interneurons in cortical and hippocampal brain areas (e.g. Chow et al., 1999, J. Neurosci. 19, 9332-9345; Martina et al., 1998, J. Neurosci. 18, 8111-8125; McDonald and Mascagni, 2006, Neurosci. 138, 537-547, Chang et al., 2007, J. Comp. Neurol. 502, 953-972), in the thalamus (e.g. Kasten et al., 2007, J. Physiol. 584, 565-582), cerebellum (Sacco et al., 2006, Mol. Cell. Neurosci. 33, 170-179; Puente et al., 2010, Histochem. Cell Biol. 134, 403-409), and auditory brain stem nuclei (Li et al., 2001, J. Comp. Neurol. 437, 196-218).
Hearing loss represents an epidemic that affects approximately 16% of the population in Europe and the US (Goldman and Holme, 2010, Drug Discovery Today 15, 253-255), with a prevalence estimated at 250 million people worldwide (B. Shield, 2006, Evaluation of the social and economic costs of hearing impairment. A report for Hear-It AISBL: www.hear-it.org/multimedia/Hear_It_Report_October_2006.pdf). In some cases, hearing loss can occur rapidly over a period of hours or days. Such acute hearing loss may be caused by exposure to loud noise, ear infection or other idiopathic causes. The most common of these, noise-induced hearing loss was estimated to have a prevalence of 1.35% of the population in Western countries in 2009; thus affecting, for example, over 4 million Americans (Noise Induced Hearing Loss Market Report, prepared by RNID, 2009). Treatment for acute hearing loss is currently limited to oral or intratympanic administration of steroidal anti-inflammatory agents, such as dexamethasone. The steroids are typically administered as soon as possible after the symptoms of hearing loss present, and treatment is continued thereafter.
A complete picture of the effect of excessive noise on the auditory system has yet to be determined. However, the effect of excessive noise on certain parts of the auditory system has been evaluated. For example, noise trauma can result in two types of injury to the inner ear, depending on the intensity and duration of the exposure: transient attenuation of hearing acuity, a so-called “temporary threshold shift” (TTS), or a permanent threshold shift (PTS). There is growing evidence that different physiological processes might underlie the two manifestations of noise exposure, although some overlap is likely (Oishi and Schacht Expert. Opin. Emerg. Drugs. 2011 June; 16(2): 235-245).
TTS is a temporary shift of the auditory threshold which causes a temporary loss of hearing. Hearing generally recovers within 24-48 hours (Humes et al. Noise and military service implications for hearing loss and tinnitus. Washington, D.C.: National Academies Press; 2005). PTS is more generally associated with long-term exposure to noise. However, depending on the intensity, frequency and duration of the noise event, permanent hearing loss (PTS) may occur after a single, isolated noise event. Furthermore, even if a noise event apparently results in a TTS (i.e. hearing appears to recover without intervention) a mouse model has indicated that TTS at young ages accelerated age-related hearing loss, even though hearing thresholds were completely restored shortly after the TTS (Kujawa et al. J. Neurosci. 2006; 26:2115-2123. [PubMed: 16481444]).
The changes in the inner ear which lead to the auditory threshold shift are not well understood, but it is thought that intense noise can cause mechanical damage (via vibration) and/or metabolic stress that triggers hair cell death (Slepecky. Hear. Res. 1986; 22:307-321 [PubMed: 3090001]; Hawkins et al. Audiol. Neurootol. 2005; 10: 305-309 [PubMed: 16103641]; Henderson et al. Ear Hear. 2006; 27:1-19 [PubMed: 16446561]). Current theories of metabolic damage centre on the formation of reactive oxygen species (free radicals, ROS) evoked by excessive noise stimulation, followed by activation of apoptotic signalling pathways to cell death. ROS emerge immediately after noise exposure and persist for 7-10 days thereafter, spreading apically from the basal end of the organ of the Corti, thus widening the area of damage (Yamane et al. Eur. Arch. Otorhinolaryngol. 1995; 252:504-508 [PubMed: 8719596]). As such, a window of opportunity potentially exists for post-exposure intervention to prevent hearing loss. Upon exposure to excessive noise, Ca2+ levels have also been observed to increase and cochlear blood flow has been observed to decrease, therefore these parameters have also been implicated in hair cell damage (Oishi and Schacht Expert. Opin. Emerg. Drugs. 2011 June; 16(2): 235-245).
A variety of treatments for preventing hair cell death have been investigated in animal models. For example, antioxidants have been found to attenuate noise-induced hearing loss when applied prior to noise exposure, and treatments up to 3 days after exposure were also found to be effective to some degree (Oishi and Schacht Expert. Opin. Emerg. Drugs. 2011 June; 16(2): 235-245).
The physical damage to the inner ear caused by exposure to excessive noise results in reduced or altered activity in the auditory nerve, which can lead to changes in the central auditory system. These changes can result in a range of hearing loss symptoms in addition to the shift in hearing threshold. For example, tinnitus may follow as a result of adaptive changes in central auditory pathways from brainstem to auditory cortex (Roberts et al., 2010, J. Neurosci. 30, 14972-14979). Changes in the central auditory processing system could also result in the impairment of auditory temporal processing, thereby causing difficulties in speech perception. Central auditory mechanisms also feedback to the outer hair cells of the cochlea, via the medial olivocochlear pathway, and can up or down-regulate the sensitivity of the cochlea to sound. Damage to this feedback mechanism following noise trauma may affect how the cochlea responds to loud sounds, and could render the cochlea more vulnerable to future damage.
However, although the use of pharmaceutical protectants to prevent/reduce inner ear damage has shown some promise in animal models, the primary preventative strategy for avoiding noise-induced hearing loss in humans is still the use of physical ear protectors such as ear plugs. Shielding the ears from noise may be undesirable, particularly in industrial and military settings where sensory perception via hearing is critical. Thus, there is a need for an effective preventative approach to noise-induced hearing loss in the form of a pharmaceutical compound. Suitably, the compound can be administered safely by the oral route.
Kv3.1 and Kv3.3 channels are expressed at high levels in auditory brainstem nuclei (Li et al., 2001, J. Comp. Neurol. 437, 196-218), and by neurons of the auditory nerve, which transmits auditory information from the cochlea to the auditory brainstem. Phosphorylation of Kv3.1 and Kv3.3 channels in auditory brainstem neurons is suggested to contribute to the rapid physiological adaptation to sound levels that may play a protective role during exposure to noise (Desai et al., 2008, J. Biol. Chem. 283, 22283-22294; Song et al., Nat. Neurosci. 8, 1335-1342). Furthermore, a loss of Kv3 channel function has been shown to be associated with noise-trauma induced hearing loss (Pilati et al., 2012, Hear. Res. 283, 98-106), and may contribute to the adaptive changes that give rise to tinnitus in many patients following noise-induced hearing loss. As discussed above, tinnitus may follow noise-induced hearing loss as a result of adaptive changes in central auditory pathways from brainstem to auditory cortex. Kv3.1 channels are expressed in many of these circuits and, along with another Kv3 channel subtype, the Kv3.2 channel, also contribute to the function of GABAergic inhibitory interneurons that may control the function of mid-brain and cortical circuits involved in auditory processing.
These data support the hypothesis that modulation of Kv3.1, Kv3.2, and/or Kv3.3 channels on neurons of the central auditory pathways could have a therapeutic benefit in patients suffering from permanent hearing loss caused by noise exposure.
Patent applications WO2011/069951, WO2012/076877 and WO2012/168710 (application number PCT/GB2012/051278) disclose compounds which are modulators of Kv3.1 and Kv3.2.
Thus, there is a continuing need for new methods for:
                preventing or reducing the development of a permanent shift in the auditory threshold after noise exposure; and/or        preventing or reducing the development of permanent tinnitus after noise exposure; and/or        preventing or reducing the development of permanently degraded central auditory processing after noise exposure.        
The present inventors have found that, surprisingly, modulation of Kv3.1, Kv3.2 and/or Kv3.3 channels in higher auditory circuits may be beneficial in preventing or limiting the establishment of a permanent hearing loss resulting from acute noise exposure. The benefits of such prevention may be observed even after administration of the pharmaceutical compounds has been ceased.